SUMMARY Rhinovirus (RV) infection causes the common cold, and is a major trigger of asthma exacerbations in allergic patients. Clinical and epidemiological data suggest that IgE conditions the allergic host to respond differently to RV. This includes a link between higher IgE levels and (1) increased risk of wheezing provoked by infection in children; and (2) worse respiratory symptoms in adult asthmatics after experimental infection. The decreased incidence of asthma exacerbations in children treated with anti-IgE supports a critical role for IgE in virus- induced asthma; however, its mode of action, particularly in the adaptive response, remains enigmatic. In the allergy field, IgE is widely held to promote Th2-driven inflammation. By contrast, outside the field, this molecule has recently been implicated in Th1-driven pathologies. In line with this latter concept, precise tetramer tracking of virus-specific T cells during infection revealed amplified Th1 responses in asthmatics with high IgE compared with non-allergic subjects. These results, along with increased Th1-promoting factors in the airways of wheezing children who have high IgE, contradict the prevailing viewpoint that anti-viral responses are deficient in allergic asthma. We hypothesize that RV amplifies type 1 responses in allergic asthma via an IgE/interferon axis mediated by plasmacytoid dendritic cells (pDC). This theory is based on the following preliminary data from allergic asthmatics infected with RV-A16: (1) increased numbers of circulating virus- specific Th1 cells compared with healthy non-allergic controls; (2) the synchronized mobilization of T and B cells expressing the Th1 lineage-specifying transcription factor, T-bet; and (3) emergence of ??T cells 3 weeks after infection coincident with worsening of symptoms, after virus has cleared. These changes are associated with expansion of pDC, which are a major source of interferons. Notably, surface levels of IgE receptor on pDC correlate with total IgE, and anti-IgE treatment preferentially abolishes receptor expression in this cell type. We are uniquely poised to test our hypothesis owing to the availability of specimens from allergic asthmatics who were experimentally infected with RV-A16 and pre-treated or not with anti-IgE. This model, coupled with state- of-the-art single-cell analytical tools, enables monitoring of the immune response to RV in a precisely time- controlled fashion. The proposed work applies high-dimensional immunophenotyping to identify dynamic fluxes in complex cell networks in order to construct a comprehensive view of type 1 responses, and to assess which facets are IgE-dependent. Single-cell gene expression profiling of RV-specific T cells will be performed to identify genes that contribute to a pathogenic Th1 response in asthma. Finally, we will interrogate the IgE/interferon axis by monitoring interferon signaling in pDC during RV infection, and its attenuation with anti-IgE therapy. In vitro assays will be used to corroborate a synergistic effect of IgE and RV pathways on interferon production in pDC, and downstream Th1 responses. Study outcomes will identify new immune targets for future research and treatments related to RV-induced asthma exacerbations.